Supplements for Longevity & Their Efficacy | Dr. Peter Attia

The episode is built around a single question: whether molecules in the so-called NAD pathway are worth taking to improve healthspan and lifespan. Huberman introduces Attia as a clinician known to systematically review the research literature and the clinical trials, and who maintains an avid clinical practice, which is why he is the chosen interlocutor for deciding whether a particular molecule, supplement, or prescription drug is something we should be thinking about and perhaps even taking. The stated scope is a comparison of NR, NMN, direct infusions, and orally taken NAD, judged on what is known and what is not known about their ability to get into cells and any efficacy they may have for longevity or healthspan. Huberman also flags that the two hosts will disclose whether they themselves take NAD, NMN, or NR and the reasons for it, and will each go through their own supplement regimen, so the personal-disclosure frame is announced at the outset rather than delivered as a conclusion.

Huberman's opening taxonomy of four broad categories of approaches for people who want to live as long as possible: (1) the do's and don'ts, including moving appropriately and often enough with zone two cardio and resistance training, keeping nerve-to-muscle connections strong, avoiding immobility and falls, eating right, and knowing one's genetics; (2) calories, glucose, and insulin, which he funnels into mTOR (mammalian target of rapamycin), with caloric restriction and rapamycin as the associated tools; (3) targeting specific cellular pathways deemed potentially interesting for longevity, namely the NAD pathway, with NR, NMN, and NAD as the major players; (4) the do-everything, even-the-most-esoteric-of-things category, described as rarer and illustrated by Bryan Johnson, who takes very high doses of polyphenols, confines caloric intake to the early part of the day with a final bite at 11:00 a.m., and uses red light and PRP (platelet-rich plasma) in a kitchen-sink approach.

A provocative thread in Huberman's framing is the claim that development is itself a form of aging. He notes that mTOR is robustly expressed during development in essentially all cells and then tapers off across the lifespan, and argues that infancy through puberty is one of the most rapid phases of aging of our entire lifespan, because we tend to treat youth as a kind of timestamp rather than as a verb. He points to how different a person looks at five, eight, and fifteen as evidence. Attia corroborates with a personal data set: he has photographed his daughter every year at the minute of her birth, holding a clock reading 3:56 at 3:56 p.m., and reports that the biggest changes are in about the first 10 years, while the differences between 13 and 14, 14 and 15, and 15 and 16 become incrementally less and less. Huberman adds that the same brain has to learn an entirely new body every year in terms of how to move it and of limb length.

Attia does not accept the taxonomy as given. He says he likes categories to be more MECE, mutually exclusive, collectively exhaustive, and reframes the first bucket as essential behavioral things that you have no choice but to engage in: you have to eat, sleep, and move, and the only choice is whether you do those things in a manner that promotes health or erodes health. Within movement he distinguishes zone two, which maximizes fat oxidation, from maximal aerobic effort, and from work that uses resistance and gravity against you. He then reserves a separate category for the molecules one would exogenously take to try to impact any of those systems, and is explicit that this is a matter of personal framing rather than a claim that Huberman's scheme is wrong: he says he is not saying his framework is correct and the other is not, only that it is how he thinks about it. Huberman's follow-up question, aside from food, what exogenous molecules do you take, pivots the conversation to that second category.

Attia's answer separates disease-specific drugs from a longevity bet. He takes a PCSK9 inhibitor, bempedoic acid, and an SGLT2 inhibitor, and at least one agent purely on the belief of its capacity in geroprotection, which is rapamycin; he also regards the SGLT2 inhibitor as probably broadly geroprotective, citing the success of canagliflozin in the Interventions Testing Program (ITP). The deeper point is epistemic. Attia says his conviction about rapamycin rests far more on experimental data than on the molecular explanation for why inhibiting mTOR would stimulate autophagy or suppress senescent cells, and he contrasts this with the NAD story, where he says such experimental data are sorely lacking. When the discussion turns to which interventions have ever extended life across the four categories of eukaryotes under discussion, the answer is caloric restriction and rapamycin, which he calls a very important point.

You see something that you don't see for a single other molecule, which is uniform life extension. No other molecule has done this. It's very important to understand there are only two interventions, full stop, that have ever extended life across those four categories of eukaryotes.

The evidence Attia privileges is comparative: administration of rapamycin or its analogs such as everolimus to organisms as close as possible to the species of interest, namely us, meaning mammals such as mice and small primates, fruit flies, worms, and even yeast, which he ranks as least important because it is so far from us. He stresses that the model matters, that in an ideal world one wants a mouse model that is not inbred and more closely related to what we care about, and that seeing many labs reproduce the same result regardless of how they do it is what makes a signal believable. The conspicuous gap is a higher-order mammal. He is waiting on Matt Kaeberlein's dog aging study, described as an exciting readout in 2026, and on another trial in mammals out of the University of San Antonio. He frames 2026 as a decision point: either a lot more conviction about taking rapamycin and prescribing it to some of his patients, though again not most, or a second look in which he might conclude that maybe they just should not be taking it, because the dog study is going to be more telling.

On the personal-protocol side, the dose is eight milligrams once a week for as long as he can tolerate it, but he usually has to take breaks. The limiting toxicity is vicious aphthous ulcers, little mouth sores, which Huberman glosses as canker sores; Attia estimates that about 10% of people get them. He reads the adverse effect as an ironic kind of quality control, remarking that it is paradoxically the only biomarker we probably have and that he secretly rejoices in knowing he is at least getting a good batch of rapamycin, and Huberman reframes the inference as resting on the side effect itself. Operationally the cycling settles into two months on and one month off, repeated, or thereabouts. Huberman states the intended mechanism as limiting mTOR so that cells grow less and mature slower, thereby slowing down aging. Subjectively, Attia reports feeling nothing on the drug apart from the sores, which fortunately are not that frequent; he says only a very few of his patients take it, floating a figure of maybe 10% and then immediately walking it back, and says he has probably heard two people claim they feel better on it but does not know what to make of it, allowing that it may just be a placebo effect.

Huberman raises a structural limitation on that evidence pipeline: he had understood the dog study was halted because of a lack of federal funding. Attia corrects this, saying it is going to go on, but confirms that initially there was insufficient funding to do the study in an adequate way and a shortfall of about two and a half million dollars for the study Matt Kaeberlein really wanted to do, which a group of them, including Attia and a few of his patients, raised. The more serious loss, in Attia's view, was that the NIH pulled back funding for the ongoing surveillance program that would allow this type of work to continue and permit greater follow-up, a decision he calls inexplicable and totally incorrect. He argues it is hard to believe there is a more interesting question in biology right now than whether a drug that seems so promising is something we should all be taking, and calls it a mystery why we would not want to know. Huberman, drawing on many years on NIH study sections, notes that the process is designed to target the best and most exciting work but now tends to fund work that is already mostly completed, and he declines to turn the exchange into a full journal-club discussion of funding.

When Huberman asserts that NAD is in essentially every cell of the body except red blood cells, Attia does not simply agree. He says he does not even know if it is in red blood cells, that his intuition is that it might be, and that he has never looked, to be honest. His reasoning is that red blood cells have a different metabolic pathway and are purely glycolytic, so they would not have the need for it in the way other cells would, but because they still undergo redox potential, it is possible NAD is in every single cell. Huberman's characterization of NAD as generally thought to be associated with energy production and mitochondrial pathways in every single cell sets up Attia's more precise biochemical account, and the exchange itself is a small example of the uncertainty the hosts are willing to leave on the record.

Attia's central distinction is between NAD as a cofactor and NAD as a substrate. He calls NAD one of the most ubiquitous molecules in the body and says that somewhere between five and six hundred pathways utilize it as a cofactor, meaning it is not consumed in a chemical reaction but serves as an electron shuttle: NAD and NADH basically play catch with electrons, and that is 99% of what NAD is doing. For that reason its levels are so tightly regulated across all ages and all physiologic conditions, in a super tight band, which he compares to the tight regulation of glucose and of pH: outside a narrow band, below seven or above 7.8 on a 0 to 14 scale, we die, full stop. The small remaining fraction is used as an actual substrate by sirtuins, which consume NAD in the process of DNA repair, and Attia identifies this as where the story picks up and, Huberman adds, where the story began.